Tumor suppressor Chk2 is a kinase essential for p53 transcriptional and apoptotic activities. Although mutations of p53 is present in more than half of all tumors, mutations of Chk2 in cancers are rare suggesting that Chk2 may be inactivated by unknown alternative mechanisms. Investigated one such alternative mechanism using acute promyelocytic leukemia (APL) as a model. Although p53-inactivating mutations are extremely rare in APL, t(15;17) chromosomal translocation which fuses retinoic acid receptor (RARalpha) to PML (promyelocytic leukemia) is almost always present, while the other PML allele is intact. We find that in normal cells, PML concentrates a subset of Chk2 into PML nuclear bodies and facilitates its autophosphorylation step, an essential step for Chk2 activity that occurs after phosphorylation of Thr68 by the upstream kinase ATM (ataxia telangiectasia mutated). In APL, PML/RARalpha suppresses Chk2 by dominantly inhibiting the autophosphorylation step. Inactivation of PML/RARalpha with all-trans retinoic acid (ATRA) restores Chk2 localization and autophosphorylation. Thus, by fusing PML with RARalpha, the APL cells have converted a Chk2 activator to a dominant suppressor compromising the Chk2-p53 apoptotic pathway. We also discovered that Chk2 is also inactivated when cells are in low energy producing states, like hypoxia or after treatment with 2-deoxyglucose (2-DG), which decreases ATP. Although the upstream ATM kinase activity is not affected under these conditions, phosphorylation of Thr68 and autophosphorylation are decreased after DNA damage in low energy states. Okadaic acid treatment reversed the inhibition of the Chk2 phosphorylation suggesting that a phosphatase mediates the inactivation of Chk2 in low energy states. Furthermore, with hypoxia or 2-DG treatment, PML cannot recruit Chk2 into PML nuclear bodies and PML-Chk2 interaction disappears. The loss of PML-Chk2 interaction in low energy states may explain the inhibition of the autophosphorylation step. Taken together, our results suggest that even without Chk2 mutation, Chk2 activity and Chk2-mediated apoptosis can be indirectly inhibited by PML disruption, which occurs with PML/RARalpha translocation, as well as by low energy environment.